The goal of this project is to advance my training in order to further understand the mechanisms underlying complement-mediated B cell activation that are important in autoimmune disorders where complement and antibodies play an important role in pathogenesis. This career development grant will become a major step forward in my transition to an independent researcher. University of Colorado Health Sciences Center provides an excellent academic training environment and research facilities that will be very important for the overall success of this project. A team of consultants from other Departments and Institutions, who are leading experts in the proposed area of research, will provide an invaluable contribution to the progress of this project and my training during the award period. Through its interactions with specific receptors on B cells, complement cleavage products such as C3d can greatly amplify signals transmitted through the binding of C3dg-attached antigen with its specific B cell antigen receptor. Our preliminary data indicate that there are important differences between the mechanisms of complement-dependent and -independent B cell activation. This project focuses on novel mechanisms of complement-mediated B cell activation on molecular, cellular and organ levels and will provide new insights into the role of complement receptors in B cell immune synapse formation, calcium signaling, trafficking of B cells in lymphoid organs and their interactions with other cells of immune system. The results will facilitate new therapeutic approaches for targeting intrinsic B cell signaling mechanisms in order to manipulate complement-mediated B cell immune responses and B cell development abnormalities that lead to autoimmune activation.